The use of an antibody, which binds to a protein expressed on a cell surface and is capable of leading the cell to death or toxicity, has been attempted in the treatment of cancer, etc. At present, a chimeric antibody (Rituximab) targeting CD20, which is a receptor existing on a cell membrane, and a monoclonal antibody such as a humanized antibody targeting Her2/neu are used in the treatment of malignant tumors, and their therapeutic effects are acknowledged. An antibody is characterized by a long serum half-life and high specificity for an antigen, and thus is particularly useful as an anti-tumor agent. For example, when an antibody targeting a tumor-specific antigen is administered, accumulation thereof in the tumor is presumed. Thus, an attack by the immune system due to the complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) on cancer cells can be expected. Binding of a radionuclide or an agent such as a cytotoxic substance to the antibody enables the effective transmission of the bound agent to a tumor site. This also reduces the amount of the agent reaching other non-specific tissues, and thus reduced side effects can be expected. When a tumor-specific antigen has activity for inducing cell death, an agonistic antibody is administered. In contrast, when a tumor-specific antigen is associated with growth and survival of cells, a neutralizing antibody is administered. This can result in the accumulation of tumor-specific antibodies and arrest or regression of tumor growth due to the activity of the antibody. As mentioned above, antibodies are considered suitable for application as anti-tumor agents because of their features.
Recently, significant anti-tumor effects of Rituximab have been exhibited with respect to B-cell lymphoma, and the side effects thereof are limited. Since Rituximab is a chimeric human-mouse protein, however, the antigenicity of Rituximab itself is strong, an antibody against a mouse moiety is produced inside the body, and the effect could be deteriorated. For some types of cancer, the therapeutic effect of Rituximab is low with the use of Rituximab alone, and the combined use thereof with an anticancer agent is currently being clinically examined (see McLaughlin P. et. al., J Clin Oncol. (1998), 16, 2825–2833; Coiffier B. et al., Blood (1998), 92, 1927–81). Accordingly, a novel anti-tumor antibody targeting an antigen is needed, and a monoclonal antibody against HLA-DR, which is a class II major histocompatibility complex (MHC) molecule, can be expected to have clinical anti-tumor activity as an antibody that recognizes an antigen different from that recognized by Rituximab.
In contrast, class II major histocompatibility complex (MHC) molecules bind to antigen peptide fragments and present these antigen peptide fragments to helper (CD4+) T-cells (“Th” cells) (see Babbin B. et al., Nature (1985), 317, 359–361). A monoclonal antibody that is specific for the class II MHC molecules is reported as a very potent selective inhibitor against the immune response of Th cells in vitro (see Baxevanis C N, et. al., Immunogenetics (1980), 11, 617–625). Since this monoclonal antibody was discovered, it has been considered to be an agent that can be used in the selective immunosuppressive therapy of autoimmune diseases such as chronic rheumatism. Based on the initial in vivo research, significant effects of these monoclonal antibodies on Th cellular heterogeneity and autoimmune response have been elucidated (see Rosenbaum J T. et al., J. Exp. Med. (1981), 154, 1694–1702; Waldor M K. et al., Proc. Natl. Acad. Sci. USA (1983), 80, 2713–2717; Jonker M. et al., J. Autoimmun. (1988), 1, 399–414; Stevens H P. et al., Transplant. Proc. (1990), 22, 1783–1784). Further, as a result of research using primates, it was discovered that graft-versus-host disease in homograft was suppressed (Billing R. & Chatterjee S. (1983), Transplant. Proc., 15, 649–650; Jonker M. et al., Transplant Proc. (1991), 23, 264–265).
Currently, immunological rejection at the time of organ transplantation is clinically suppressed using immunosuppressive agents such as cyclosporin A or FK506. A disadvantage of these immunosuppressive agents is that potent side effects are caused by the non-specific suppression of the immune response.
Accordingly, antibodies are considered suitable for use as immunosuppressive agents with few side effect because of their features.